Single-cell image-based screens identify host regulators of Ebola virus infection dynamics.

Journal: Nature microbiology
Published Date: Jul 24, 2025

Abstract

Filoviruses such as Ebola virus (EBOV) give rise to frequent epidemics with high case fatality rates while therapeutic options remain limited. Earlier genetic screens aimed to identify potential drug targets for EBOV relied on systems that may not fully recapitulate the virus life cycle. Here we applied an image-based genome-wide CRISPR screen to identify 998 host regulators of EBOV infection in 39,085,093 cells. A deep learning model associated each host factor with a distinct viral replication step. From this we confirmed UQCRB as a post-entry regulator of EBOV RNA replication and show that small-molecule UQCRB inhibition reduced virus infection in vitro. Using a random forest model, we found that perturbations on STRAP (a spliceosome-associated factor) disrupted the equilibrium between viral RNA and protein. STRAP was associated with VP35, a viral RNA processing protein. This genome-wide screen coupled with 12 secondary screens including validation experiments with Sudan and Marburg virus, presents a rich resource for host regulators of virus replication and potential targets for therapeutic intervention.

Authors

  • Rebecca J Carlson
    Massachusetts Institute of Technology, Department of Health Sciences and Technology, Cambridge, MA, USA.
  • J J Patten
    Department of Virology, Immunology, and Microbiology, Boston University School of Medicine, Boston, MA, USA.
  • George Stefanakis
    Laboratory for Information & Decision Systems, Massachusetts Institute of Technology, Cambridge, MA 02139.
  • Brian Y Soong
    Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Adityanarayanan Radhakrishnan
    Department of Electrical Engineering and Computer Science, Laboratory for Information and Decision Systems, Institute for Data, Systems and Society, MIT, Cambridge, MA, USA.
  • Avtar Singh
    Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Naveen Thakur
    Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Kathleen C F Sheehan
    Department of Pathology and immunology, Washington University School of Medicine, St Louis, MO, USA.
  • Gaya K Amarasinghe
    Department of Pathology and immunology, Washington University School of Medicine, St Louis, MO, USA.
  • Nir Hacohen
    Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Christopher F Basler
    Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • Daisy W Leung
    Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
  • Caroline Uhler
    Department of Electrical Engineering and Computer Science, Laboratory for Information and Decision Systems, Institute for Data, Systems and Society, MIT, Cambridge, MA, USA. cuhler@mit.edu.
  • Robert A Davey
    Department of Virology, Immunology, and Microbiology, Boston University School of Medicine, Boston, MA, USA. radavey@bu.edu.
  • Paul C Blainey
    Broad Institute of MIT and Harvard, Cambridge, MA, USA.

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